Management of Atopic Dermatitis: The Role of Tacrolimus

Atopic dermatitis (AD) is a long-lasting inflammatory dermatological condition characterized by itchy, eczematous, sparsely tiny blisters that hold a clear watery substance. Additionally, the diseased skin can suppurate, occasionally with weeping with thickening of the affected skin. This is considered one of the top skin disorders involving both children and adult populations globally. The principal therapeutic intervention for AD is long-standing topical glucocorticoids, which have been used for several decades. Corticosteroid therapy brings several adverse drug effects (ADRs), including irreversible skin atrophy. Tacrolimus belongs to the class of calcineurin inhibitors, which is a type of immunomodulator possessing promising efficacy in treating AD. Topical tacrolimus is an effective and safe non-corticosteroid substitute treatment for AD. We reviewed the available literature to compare and institute the safety, efficacy, and effectiveness of tacrolimus when equated to corticosteroid therapy in managing AD.


Introduction And Background
Tacrolimus is a very potent anti-T-lymphocyte, macrolide, and immunosuppressant medicine produced from the fungus Streptomyces tsukubaensis; it was discovered in 1984 [1][2][3]. It has been reported that the therapeutic interventions for atopic dermatitis (AD) have vastly changed after the advent of tacrolimus [4]. The topical application of tacrolimus at a concentration of 0.03% to 0.1% has been reported to possess effectiveness therapeutically among pediatric (middle childhood [2-6 years] and school aged [7-15 years] children) and adult patients [4][5][6]. A lower concentration (0.03%) in the pediatric age cluster is recommended and is contraindicated in the usage below two years of age [7].

Diverse role of tacrolimus as an immunomodulator in transplant and dermatology
The concept of substituting poorly or not functioning vital body parts or tissues with physiologically healthy (homologous) ones is an old concept [8,9]. Nevertheless, in 1954, the first effective and efficient human renal transplant was achieved [9]. In the last 70 years, there has been a massive improvement in transplantrelated surgical methods, instruments, and organ conservation [9][10][11][12]. Comprehensive pathophysiological knowledge regarding immunologic barriers to transplantation has improved immensely. [12,13] The progress of novel immunosuppressive agents with higher potent effects was the principal driving force for the human organ transplantation routine [8,14,15]. The current success of transplantation and prolonging human life is often notified because of tacrolimus (FR000506/FK506) [9,[16][17][18][19]. Some multicentered studies demonstrated therapeutic safety and efficiency of systemic and topical use of tacrolimus in common inflammatory skin diseases such as psoriasis and AD, with only a few local side effects [20].

Brief Overview Atopic Dermatitis
AD is a long-lasting, reverting, exceedingly pruritic inflammatory condition, and one of the top dermatological disorders [21][22][23]. AD is considered a specific form of eczema causing intense itching and considerable sleep disorders and often promotes social stigma and increases emotional and psychological stress [24][25][26][27][28]. This dermatological disease significantly increases morbidity and destructively disturbs the patient's and family's quality of life [29][30][31][32][33]. To date, the pathology of the disease remains obscure.

Review Tacrolimus: mode of action
Dermatological tacrolimus is a useful immunomodulator [70,71]. It attaches to specific cytoplasmic immunophilin (FKBP12), Ca2+, and calmodulin, hindering or suppressing calcineurin's phosphatase activity. This further impairs the nuclear factor of activated T-cells (NFAT) signaling process by preventing its dephosphorylation, which cumbers upon interleukin-2 (IL-2) generation and results in diminished T-cell activation and inflammatory cytokine let out [72][73][74]. Topical tacrolimus reduces mononuclear cell infiltration, thereby partly bringing back hair growth and hence can be valuable in alopecia areata [20,75,76]. It is also reported that tacrolimus impedes the conglomerate of IL-2, IL-3, IL-4, tumor necrosis factor-alpha (TNF-α), and granulocyte-macrophage colony-stimulating factor (GM-CSF) [1]. Apart from these, there is also evidence that tacrolimus hinders the let-out pre-formed inflammatory molecules from mast cells and basophils present in the skin layers and minimizes the utterance of FcεRI on Langerhans cells [77,78].

Efficacy and Effectiveness
Various studies have demonstrated the benefits and ADRs of tacrolimus in contrast to either vehicle base or diverse potencies of dermal glucocorticoids. Several clinical studies have established tacrolimus's relative efficacy ( Table 1) and safety over corticosteroids [82][83][84][85][86][87][88][89]. There is abundant evidence suggesting the safety and efficacy of tacrolimus and other calcineurin inhibitors over long-term topical corticosteroid therapy for AD and other dermatological conditions [84,[90][91][92][93]. The beneficial and advantageous effects of tacrolimus were found in pediatric and adult patients with AD ( Table 1) [94]. et al. [84] 2010 RCT: AD  Multiple studies observed that individuals with tolerable to grave AD showed noticeable more overall global improvement with topical tacrolimus (0.1% and 0.03%) than with the mild-to-moderate potent dermatological glucocorticoid after seven days [95][96][97][98]. Local application of tacrolimus was found to be efficacious and had low-profile ADRs, and thus is considered mainstream medication for AD patients [99]. The most common ADRs with tacrolimus were local irritations at the application site, generally resolved with continual treatment. The findings suggested that dermal tacrolimus is an effective, safe, non-corticosteroid substitute treatment for AD [82]. A study compared 0.1% topical use of tacrolimus with glucocorticoids. The tacrolimus and its' congeners significantly improved the affected body surface area (p<0.001), higher than the steroidal cluster [98]. It was assessed through a modified eczematous area and severity index (mEASI), eczematous area, and severity index (EASI). The tacrolimus cluster suffered a higher rate (P<0.001) of a smoldering commotion than the corticosteroids. However, the skin burning resolved in one week, and no infection or malignancies were reported [98]. Topical tacrolimus 0.03% has been found as more efficacious and safer than mild corticosteroids. Besides AD, tacrolimus also showed promising efficacy in other conditions, including oral lichen planus and labial discoid lupus erythematosus [100,101].

Safety
Adverse effect profiles of both long-term and short-term corticosteroids are more serious than tacrolimus [102]. The most frequent adverse effect of topical tacrolimus includes a burning sensation on the skin or irritation. However, burning skin-related adverse effects most frequently appear in the early part of the pharmacological intervention and usually exist for short periods. It has been reported that skin irritation stops within the first few days of therapy [103]. Topical tacrolimus does not cause skin atrophy, which occurs during the treatment with topical corticosteroids [104]. Tacrolimus dermatological preparation was not associated with an increased risk of cutaneous infections (bacterial and viral infections), which usually coexist with AD [105][106][107][108]. Other cutaneous infections found due to treatment with tacrolimus include herpes simplex, varicella, and eczema herpeticum [108,109]. Many studies have warned about the potential risk of developing cancer (mainly lymphoma and skin cancer) [110][111][112]. However, other research revealed that the use of topical calcineurin inhibitors is not grounded on long-standing safety data and the information derived from animal studies [91,113,114]. However, studies do not reveal that tacrolimus raises the risk of lymphoma and melanoma skin cancer [82,91,110,[115][116][117][118][119]. Long-standing safety of dermal tacrolimus was observed in trials for up to four years [84]. A study on healthy volunteers demonstrated that tacrolimus causes almost no functional changes to healthy skin due to its poor permeability compared to topical corticosteroids [120].
The topical use of corticosteroids may cause skin atrophy; however, there was no reported possibility of malignancies or skin atrophy due to tacrolimus [83,97]. Tacrolimus effectively treats moderate-to-severe AD without causing atrophy due to prolonged use of topical corticosteroids [121].

Conclusions
AD is a continuing inflammatory dermal disease that negatively impacts the patient's quality of life. It affects both children and adults. The treatment is usually long-term and often unsatisfactory on account of the ADRs and the possibility of relapse. There has been a continuous search for a safer, efficacious therapy for long-term remission. Among the available corticosteroids, calcineurin inhibitors, emollients, antihistamines, and immunosuppressants are mentioned. This review intended to explore the efficacy and safety of tacrolimus over topical steroids. It was evident from the available trials, systematic reviews, and other studies that tacrolimus is equi-efficacious to glucocorticoids in ameliorating AD symptoms. Except for skin irritation or burning sensation, the safety profile of tacrolimus is similar to that of corticosteroids. Appropriate patient education can help patients and families overcome the fear of AD therapy. Large-scale clinical trials, systematic reviews, and meta-analyses could improve comprehension knowledge regarding the safety and efficacy of tacrolimus. This can motivate drug regulatory agencies to review the drugs' safety warnings.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.